Many advances in medicine in the 20th century have been due to the discovery of new classes of small molecular weight effectors for various therapeutic needs. Herein we disclose the diverse, but selective pharmacologically active boron-containing entities.
One hallmark of the modern era of medicine has been the decline in morbidity and mortality associated with bacterial and fungal infections. However, misuse of conventional antibiotics and natural selection of the infectious bacterial population has resulted in the development of varying degrees of drug resistance by most bacterial infectious agents to most antibiotic agents. In severe cases, such as MRSA (Multidrug-Resistant StaphA), one or only a few antibiotics are currently effective. In addition, the existence of immunodeficiency syndromes results in additional incidences of opportunistic infections requiring intensive antibiotic treatment.
Viruses are implicated in a variety of animal and human disease. Numerous approaches have been proposed to combat these pathogens which include, but are not limited to herpesviruses 1 and 2 (HSV-1 and HSV-2), influenza viruses A, B and C, parainfluenza viruses 14, syncytial virus, Epstein-Barr virus, rhinoviruses, human immunodeficiency viruses (HIV), polioviruses, coxsackieviruses, echoviruses, rubella virus, varicella-zoster virus, neuroderma-tropic virus, variola virus, cytomegalovirus, hepatitis A, B and C viruses, papoviruses, rabies virus, yellow fever virus, dengue virus, West Nile virus and SARS virus.
One approach in the development of antiviral compounds has been to identify compounds which interfere with the normal viral metabolism and replication in infected host cells. During the screening of new borinic ester compounds, we have found that certain of these compounds show antiviral activity in cell culture assay systems. Many existing compounds currently in use for treating viral diseases are subject to resistance mechanisms, are expensive to make, do not adequately treat patients or have adverse side effects. Therefore, there is a continuing need for new compounds which act to kill viruses, to inhibit viral replication or to block the pathogenic action of viruses.
Virus CategoryPertinent Human InfectionsRNA VirusesPicomaviridaePolioHuman hepatitis AHuman rhinovirusTogavindae andRubella - German measlesFlaviviridaeYellow feverCoronaviridaeHuman respiratory coronavirus (HCV)Severe acute respiratory syndrome (SAR)RhabdovindaeLyssavirus - RabiesParamyxovindaeParamyxovirus - MumpsMorbilivirus - measlesPneumovirus - respiratory syncytial virusOrthomyxoviridaeInfluenza A–CBunyaviridaeBunyavirus - Bunyamwera (BUN)Hantavirus - Hantaan (HTN)Nairevirus - Crimean-Congo hemorrhagic fever(CCHF)Phlebovirus - Sandfly fever (SFN)Uukuvirus - Uukuniemi (UUK)Rift Valley Fever (RVFN)ArenaviridaeJunin - Argentine hemorrhagic feverMachupo - Bolivian hemorrhagic feverLassa - Lassa feverLCM - aseptic lymphocyctic choriomeningitisReoviridaeRotovirusReovirusOrbivirusRetroviridaeHuman immunodeficiency virus 1 (HIV-1)Human immunodeficiency virus 2 (HIV-2)Simian immunodeficiency virus (SIV)DNA VirusesPapovaviridaePediatric viruses that reside in kidneyAdenovindaeHuman respiratory distress and some deep-seatedeye infectionsParvovindaeHuman gastro-intestinal distress (Norwalk Virus)HerpesvindaeHerpes simplex virus 1 (HSV-1)Herpes simplex virus 2 (HSV-2)Human cytomegalovirus (HCMV)Varicella zoster virus (VZV)Epstein-Barr virus (EBV)Human herpes virus 6 (HHV6)PoxvindaeOrthopoxvirus is sub-genus for smallpoxHepadnaviridaeHepatitis B virus (HBV)Hepatitis C virus (HCV)
Boron containing compounds have received increasing attention as therapeutic agents over the past few years as technology in organic synthesis has expanded to include this atom. [Boron Therapeutics on the horizon, Groziak, M. P.; American Journal of Therapeutics (2001) 8, 321-328] The most notable boron containing therapeutic is the boronic acid bortezomib which was recently launched for the treatment of multiple myeloma. This breakthrough demonstrates the feasibility of using boron containing compounds as pharmaceutical agents. Boron containing compounds have been shown to have various biological activities including herbicides [Organic boron compounds as herbicides. Barnsley, G. E.; Eaton, J. K.; Airs, R. S.; (1957), DE 1016978 19571003], boron neutron capture therapy [Molecular Design and Synthesis of B-10 Carriers for Neutron Capture Therapy. Yamamoto, Y.; Pure Appl. Chem., (1991) 63, 423-426], serine protease inhibition [Borinic acid inhibitors as probes of the factors involved in binding at the active sites of subtilisin Carlsberg and α-chymotrypsin. Simpelkamp, J.; Jones, J. B.; Bioorganic & Medicinal Chemistry Letters, (1992), 2(11), 1391-4], [Design, Synthesis and Biological Evaluation of Selective Boron-containing Thrombin Inhibitors. Weinand, A.; Ehrhardt, C.; Metternich, R.; Tapparelli, C.; Bioorganic and Medicinal Chemistry, (1999), 7, 1295-1307], acetylcholinesterase inhibition [New, specific and reversible bifunctional alkylborinic acid inhibitor of acetylcholinesterase. Koehler, K. A.; Hess, G. P.; Biochemistry (1974), 13, 5345-50] and as antibacterial agents [Boron-Containing Antibacterial Agents: Effects on Growth and Morphology of Bacteria Under Various Culture Conditions. Bailey, P. J.; Cousins, G.; Snow, G. A.; and White, A. J.; Antimicrobial Agents and Chemotherapy, (1980), 17, 549-553]. The boron containing compounds with antibacterial activity can be sub-divided into two main classes, the diazaborinines, which have been known since the 1960's, and dithienylborinic acid complexes. This latter class has been expanded to include many different diarylborinic acid complexes with potent antibacterial activity [Preparation of diarylborinic acid esters as DNA methyl transferase inhibitors. Benkovic, S. J.; Shapiro, L.; Baker, S. J.; Wahnon, D. C.; Wall, M.; Shier, V. K.; Scott, C. P.; Baboval, J.; PCT Int. Appl. (2002), WO 2002044184]. Synthetic developments described in Benkovic et al. enabled creation of a much more diverse class of unsymmetrical di-substituted borinic acid complexes not possible before.
Thus, there continues to be a need in the medical arts for novel, more effective, antibiotic compounds, especially for treating infectious diseases, that are resistant to currently available therapies.